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Humphrey LL, Johnson M, Teutsch S. Lung Cancer Screening: An Update for the U.S. Preventive Services Task Force [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2004 May. (Systematic Evidence Reviews, No. 31.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

Cover of Lung Cancer Screening

Lung Cancer Screening: An Update for the U.S. Preventive Services Task Force [Internet].

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2Background

Lung cancer is the second leading cause of cancer in the United States and the leading cause of cancer-related death among men and women. Worldwide, lung cancer and lung cancer-related deaths have been increasing in epidemic proportions, largely reflecting increased rates of smoking.2, 3 In the year 2003, the American Cancer Society predicted that there would be approximately 171,900 new cases of lung cancer diagnosed and approximately 157,200 lung cancer-associated deaths in the United States.4 Worldwide, it is estimated that there were 1 million deaths in the year 2000.5

Cigarette smoking is the major risk factor for lung cancer, causing approximately 87% of lung, bronchial, and tracheal cancers.2 Other risk factors include family history,2, 6, 7 chronic obstructive pulmonary disease,6, 8, 9 idiopathic pulmonary fibrosis,2 environmental radon exposure,2, 10 passive smoking,2, 1113 asbestos exposure,2, 10 and certain occupational exposures.2, 10, 13 In addition, for a given amount of tobacco exposure, some studies suggest that women are at higher risk than men.14, 15

By far the most important public health intervention that could reduce lung cancer incidence and deaths is changing smoking habits. Unfortunately, although overall prevalence rates of smoking have decreased in the last 2 decades, the prevalence remains high at 24%.13, 16 In the clinical setting, smoking cessation programs, even in conjunction with drug therapy, have long-term smoking cessation rates of only approximately 20–35% at 1 year among motivated volunteers in good quality studies.1719 In addition, in 1999, approximately 45.7 million adults (23.1% prevalence) were former smokers, and currently a high percentage of lung cancer occurs in former smokers since the risk for lung cancer does not decline for many years following smoking cessation.2023 Finally, household exposure to second hand smoke is substantial and also associated with lung cancer.12 These smoking exposure rates, in addition to large numbers of individuals with past or passive exposure to smoking, indicate that lung cancer will continue to be a major public health problem in the US, as well as worldwide.

Lung cancer has a very poor prognosis; it is the cause of death in more than 90% of affected individuals.24 Even with advances in therapy, 5-year survival rates are less than 15% on average for all individuals with lung cancer.25 Five-year survival is directly related to its stage at the time of diagnosis, ranging from 70% for stage I disease, to less than 5% for stage IV disease.26 Unfortunately, 75% of patients with lung cancer present with symptoms due to advanced local or metastatic disease that is not amenable to cure.24 For many of these reasons, screening for and treating early lung cancer is intellectually appealing. However, there are several important methodological issues that must be critically analyzed before considering widespread screening.

Screening Methodology

Based on traditional epidemiologic and screening methodology criteria, lung cancer in many ways meets criteria for a disease for which screening would be valuable.27 First, it is a very serious disease associated with high morbidity and mortality rates. Second, it is also a relatively prevalent disease among high-risk populations. Early studies of lung cancer screening with chest x-ray and sputum cytology among volunteers with smoking exposure indicated a disease prevalence in the range of 0.5 to 2.2%, increasing significantly with age.28, 29 These data suggest that lung cancer may have a relatively prevalent asymptomatic or pre-clinical stage which is necessary for screening to be beneficial. What is not known about lung cancer is the length of its pre-clinical phase, though it is known to vary by histologic type of lung cancer.3033

Mortality from lung cancer is closely associated with the stage of the disease at the time of diagnosis and based on this; it is assumed that early treatment with surgery is associated with better outcome. Ideally, proof of benefit from surgical treatment of lung cancer would come from randomized trials of treatment versus no treatment. However, to our knowledge these trials have not been conducted. Consequently, evaluating the effectiveness of early lung cancer treatment relies on indirect evidence of benefit. Indirect support for the relative effectiveness of surgical treatment comes from several sources. First, two natural history studies of both screen and symptom-detected unresected clinical stage I non-squamous cell lung cancer have shown that almost all patients eventually die of lung cancer34, 35 over 5–10 years. Notably, because these are clinically staged tumors, they may actually have been of higher stage with worse prognosis than pathological stage I tumors. Second, some studies have shown that individuals with residual disease or positive microscopic resection margins post-operatively have shorter survival than those with clear margins.36 Since these patients were all referred for surgery; it is likely their clinical risk assessments were similar. In one study for example, the 5-year survival of patients with stage I Non-Small Cell Lung Cancer (NSCLC) with complete resection is 54%, compared with 43% for patients with microscopic residual disease.37 Other data38 show higher survival among fully resected patients compared with partially resected patients. Another important example of the relationship between surgical resection and survival comes from literature comparing outcomes among African-Americans and Caucasians,39 where lack of surgical therapy explained a large part of the increased mortality rates experienced by African-American individuals of low income when compared with others of similar stage. Finally, other support for the effectiveness of surgical treatment is derived from literature showing improved survival among patients undergoing mediastinal lymph node removal as compared with mediastinal lymph node sampling among patients pathologically matched by stage,40 suggesting that removal of mediastinal lymph nodes improves outcome. Thus, several indirect lines of evidence support the benefit of surgically treating lung cancer and the hypothesis that early surgical treatment is associated with better outcomes than later surgical treatment.

The ideal screening test for lung cancer would have high sensitivity for detecting disease prior to metastases, high specificity, relative safety, acceptability to patients and physicians, relative low cost,27 and most importantly, would either reduce mortality, improve quality of life, or do both. Ideally, the effectiveness of a screening test will be evaluated in randomized controlled trials so that these factors and the outcomes of morbidity and mortality can be evaluated in a manner where screening biases are minimized.27 Several methodological biases are relevant to understanding screening studies.

Lead-time bias occurs when the time of diagnosis is advanced by screening but the time of death is unchanged. Thus, comparing survival rates among screened and unscreened patients can create the appearance of better outcome by prolonging survival among screenees but not altering mortality. Most effectively dealing with lead-time requires evaluation of mortality rates among screened and unscreened individuals in randomized trials. Length bias is a bias towards detecting less aggressive tumors in a population being periodically screened, and can only be dealt with in randomized controlled trials. Volunteer bias occurs because volunteers are different than non-volunteers in ways that may make the groups difficult to compare and may result in better outcomes among a screened group than would occur if a group were randomized, since the volunteers might have improved lung cancer survival in the absence of screening (compared to non-volunteers), based on healthy lifestyle or other non-randomly distributed factors. Another important screening bias is over-diagnosis, in which cancers that would never have been important during an individual's lifetime are diagnosed and treated. Because these biases can only be eliminated in randomized controlled trials with mortality as an outcome, most emphasis in public health guideline development is placed on information from randomized controlled trials.

Until recently, the only modalities for lung cancer screening that had been evaluated in large populations were chest x-ray and sputum cytology. This review discusses studies of chest x-ray, sputum cytology, and low dose computerized tomography (LDCT) scanning for lung cancer screening in both high-risk and low-risk populations. The emphasis in this review is on patient outcomes since these data are available for many of the screening modalities.

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